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BMI, Insulin Resistance Contribute to Fibrosis
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"Relationship Between Steatosis, Inflammation, and Fibrosis in Chronic Hepatitis C: A Meta-Analysis of Individual Patient Data"
Gastroenterology May 2006
Gioacchino Leandro_, Alessandra Mangia, Jason Hui , Paolo Fabris , Laura Rubbia-Brandt , Guido Colloredo#, Luigi E. Adinolfi__, Tarik Asselah, Julie R. Jonsson, Antonina Smedile, Norah Terrault, Valerio Pazienza, Maria Teresa Giordani , Emiliano Giostra##, Aurelio Sonzogni___, Giuseppe Ruggiero__, Patrick Marcellin, Elizabeth E. Powell, Jacob George , Francesco Negro ##
Received 11 July 2005; accepted 4 January 2006
Cofactors contributing to a damaged liver (fibrosis): the overweight-associated insulin resistance.....the sustained hyperglycemic/hyperinsulinemic state..... contribute further to both hepatic steatosis and fibrosis.....a BMI less than 25 kg/m2.....The beneficial effect of body-weight reduction and physical fitness on liver disease activity already has been reported in persons with CHC.....other cofactors including alcohol consumption and possibly cigarette smoking are amenable to medical management, with beneficial effects on liver disease progression....
ABSTRACT
Background & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index.
Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States.
Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age.Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation.
Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.
sDISCUSSION
Progression of CHC depends significantly on host and environmental factors. Given that currently available antiviral regimens induce a sustained virologic response in only approximately 60% of patients, and that individuals with advanced liver disease may not benefit from therapy, medical interventions often are limited to correcting cofactors associated with liver-related morbidity.
Steatosis has been suggested as an important cofactor for liver fibrosis. However, there is not a clear consensus on the relationship between steatosis and fibrosis. Some studies have reported an independent association between steatosis and fibrosis for all patients with CHC, whereas others have provided evidence that this relationship holds only for certain subgroups (ie, those infected with HCV genotype 116 or 313-16). A few reports have failed to confirm any association between steatosis and hepatic fibrosis.21,22 Because these conflicting conclusions may depend on the varying baseline features of individual patients (inclusion and exclusion criteria, age and viral genotype distribution, proportion of cirrhotic patients), we pooled patients' data from 10 databases from various centers around the world (many of whom were involved in the aforementioned studies) and conducted a meta-analysis of individual patient data. We are well aware of the limitations inherent in this kind of analysis, for example, the impossibility of properly converting the varying activity and fibrosis scores into a uniform scoring system, the lack of homogeneous data on viral load, or of the full appreciation of the impact of disease duration. Despite these limitations, our multivariate regression identified steatosis as associated with fibrosis, and this effect was independent of the participating center. The association also held for some large subgroups of patients, that is, those with genotype 1 or with a BMI less than 25 kg/m2. The conclusions, although partly conflicting with those obtained by similar analyses performed at the level of single centers (including some considered in the present study15,21,23), are not necessarily incompatible with one another. Our large dataset, however, allowed us to enter the center as a variable into the analyses, the conclusions of which are therefore independent of the population characteristics at each participating location.
Some other results worthy of comment include (1) the strong association between steatosis and genotype 3 (observed in all subgroups including the 300 obese patients and confirming previous work)11-16; (2) the association between fibrosis and histologic activity in all 4 viral genotypes examined (see later); and (3) the observation that patients with genotype 2 had less fibrosis. Although the latter was not found in the univariate analysis (ie, presence and level of activity in these patients were not different from those found in patients with other genotypes), suggesting a possible statistical artifact, we consider that it may be worth further study because a possible association between genotype 2 and slower disease progression was suggested in an earlier report.24
Assuming that the steatosis/fibrosis association entails a causative link between fatty liver and fibrogenesis, proper clinical management should address the pathogenesis of a fatty liver and/or the mechanisms that make steatosis a fibrogenic risk factor. According to our data the association holds essentially for genotype 1-infected patients, in whom fat accumulation is not determined by HCV replication, as shown by the total or partial lack of a response to antivirals.25,26 Conversely, in these same persons, a correlation has been established between the severity of steatosis and metabolic features such as BMI,12 and such an association was confirmed by our analysis. Thus, correction of an increased BMI should be advised strongly in patients with CHC, especially those with advanced fibrosis. The beneficial effect of body-weight reduction and physical fitness on liver disease activity already has been reported27,28 in persons with CHC. Likewise, other cofactors including alcohol consumption2 and possibly cigarette smoking29 are amenable to medical management, with beneficial effects on liver disease progression.
It is noteworthy that steatosis was not associated with fibrosis in patients who were overweight or obese, suggesting that the link may be indirect and conditional on other cofactors. We suggest that, to explain the relationship between steatosis, fibrosis, and metabolic factors, a prominent role is played by liver inflammation. This conclusion is based primarily on the observation that (1) the presence of necroinflammatory activity was associated independently with fibrosis and steatosis, both overall and in the 2 subgroups (ie, patients with genotype 1 and in lean patients [BMI <25 kg/m2]), and that (2) whenever the analysis addressed the factors predicting steatosis, a lack of association with fibrosis was paralleled by a lack of association with activity. We propose that the link between hepatic steatosis and fibrosis is indirect, perhaps through the induction of proinflammatory and hence profibrotic mediators such as tumor necrosis factor, free fatty acids, osteopontin, and interleukin-6. Thus, hepatic (and/or peripheral) steatosis may render the liver more vulnerable to injury, inflammation,30 and apoptosis.31 In a recent study, CHC without steatosis was not associated with stellate cell activation or fibrosis.31 In contrast, in the presence of steatosis, there was an association with increased apoptosis, stellate cells activation, and fibrosis.31 Thus, liver inflammation would be responsible in part for the steatosis, and amplified by it. Furthermore, the overweight-associated insulin resistance, via free fatty acid overflow to extra-adipose tissues32 and the sustained hyperglycemic/hyperinsulinemic state,22,33,34 would contribute further to both hepatic steatosis and fibrosis.
In conclusion, we propose that steatosis is associated with fibrosis in CHC via the inflammatory reaction that accompanies steatosis and CHC infection. The simultaneous occurrence of an overweight/insulin resistance syndrome with chronic hepatic inflammation may represent a risky environment for the liver. Because exercise already has been shown to have a beneficial effect on liver disease parameters,30 strategies aiming to correct being overweight and obese and that encourage physical activity should become a mainstay in the management of patients with CHC.
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